3-BC, early postnatal survival rate, and thymus weight by both compounds at higher doses. 4-MBC and 3-BC delayed male puberty and dose-dependently affected reproductive organ weights of adult male and female F1 offspring, with partly different effect patterns. Thyroid weight was increased by higher 4-MBC doses. Tissue-specifi c changes in mRNA levels of estrogen-regulated genes in the prostate, uterus, and brain regions, determined by real-time PCR, in their response to acute estradiol challenge in adult gonadectomized offspring were observed. Lowest effective doses were 0.24 mg/kg/day for 3-BC and 7 mg/kg/d for 4-MBC. Fat tissue levels at 7 mg/kg 4-MBC (GC–MS) approached the range of UV fi lters in fi sh. A human SED of 4-MBC has been estimated as 0.23 mg/kg body weight. Such a dose would be only 1/3 of the present no observed adverse effect level (NOAEL) and 1/30 of the lowest observed adverse effect level of 4-MBC (2,29). Other researchers al so came to the conclusion that various metabolic factors, such as fat and lipid homeostasis and thyroid hormone production, mediated by non–estrogen-related methods, were affected by OMC and 4-MBC. OMC and 4-MBC in rats were shown to exert endocrine disrupting, including uterotrophic, i.e., estrogenic effects. Estrogens also have metabolic effects therefore, the impact of oral application of the two UV absorbers at two doses (50 or 250 mg per 20 g food of OMC or 4-MBC, respectively) for 3 mo on lipids and hormones was compared with that of estradiol-17β (E2). E2, OMC, and 4-MBC reduced weight gain, the size of fat depots, and serum leptin, a lipocyte-derived hormone, when compared with the ovariectomized control animals. Serum triglycerides were also reduced by the UV screens but not by E2. On the other hand, E2 and OMC re- duced serum free fatty acids and cholesterol low-density lipoproteins, and high-density lipo- proteins this effect was not shared by 4-MBC. Whereas E2 inhibited, OMC and 4-MBC stimulated serum LH levels. In the uterus, both UV fi lters had mild stimulatory effects. 4-MBC inhibited serum T4, resulting in increased serum thyroid-stimulating hormone (TSH) levels. On the basis of human data, the applied doses for experimental animals were relevant as they also resulted in μM concentrations (30). Wang et al. (31) conclu ded that 4-MBC acted as a possible inhibitor of the pituitary–thyroid axis, as the TSH serum levels were found to be considerably high. Moreover, the weight of the thyroid glands was considerably increased. Cinnamate derivatives interfered with the TH axis in rats. The perinatal OMC exposure induced adverse effects on the reproductive and neurological development of rat offspring. The treatment with OMC for 12 weeks caused a decrease in T4 level in the blood of ovariectomized female rats and inhibited the activity of 5′-deiodinase that converts T4 to T3 in the liver [mean intake of test substances (mg/animal/ day): OMC, 2.5 (low) or 12.5 g/kg (high) 4-MBC, 2.5 (low) or 12.5 g/kg (high)]. Experimental studies refer ring to human exposure showed that BP-3, 4-MBC, and OMC rapidly permeated intact skin and could be detected in plasma after 1–2 h following application. Interestingly, the concentrations of these compounds in the same experimental study in male urine and plasma were higher than those in female samples, indicating a gender difference in the metabolism, distribution, and possibly also in the accumulation of UV fi lters in adipose tissue. Was it an effect of surface? Male body has larger surface than female body. If the sunscreen was applied at the same mg/cm2 concentration, more surface equates to more sunscreen applied, hence more sunscreen in urine and plasma? The concentrations that were used in every experiment were different. A single blinded experimental study in Denmark used 10% concentration of BP-3, 4-MBC, and OMC (whole-body application of sunscreen 2 mg/cm2). In Sweden, an experimental study used 4% of BP-3 (whole-body application of sunscreen 2 mg/cm2) (32). DISTRIBUTION OF UV FILTERS ON THE SKIN 305

Randomized clinical trial at a cl inical pharmacology unit (West Bend, Wisconsin) was conducted in 48 healthy participants. Systemic absorption and pharmacokinetics of six active ingredients (avobenzone, oxybenzone, octocrylene (OCR), homosalate, octisalate, and octinoxate) in four sunscreen products under single- and maximal-use conditions were assessed. Participants were randomized to one of four sunscreen products, formu- lated as lotion (n = 12), aerosol spray (n = 12), nonaerosol spray (n = 12), and pump spray (n = 12). The sunscreen product was applied at 2 mg/cm2 to 75% of the body surface area at 0 h on day 1 and three times on day 2 through day 4 at 2-h intervals, and 34 blood samples were collected over 21 d from each participant. In this study, all six of the tested active ingredients were systemically absorbed and had plasma concentrations that sur- passed the FDA threshold for potentially waiving some of the additional safety studies for sunscreens. Geometric mean maximum plasma concentrations of all six active ingredients were greater than 0.5 ng/mL, and this threshold was surpassed on day 1 after a single application for all active ingredients (33). Levels of UV fi lters measured in human seminal fl uid and comparisons to levels mea- sured in concurrently collected urine and serum samples were presented. In total, nine UV fi lters were analyzed by TurboFlow-LC–MS/MS (Thermo Fisher Scientifi c, San Jose, CA) in paired urine, serum, and seminal fl uid samples from 300 young Danish men from the general population each man collected one of each sample type within 1 h. Four of the examined UV fi lters could be detected in seminal fl uid sam- ples at levels above limit of detection in more than 10% of the samples. BP-1 and BP-3 were most frequently detected in, respectively, 18%, 19%, and 27% of the seminal fl uid samples albeit at levels one to two orders of magnitude lower than the levels observed in urine. 4-MBP was detectable in 11% of the seminal fl uid samples, whereas in 5% of the urine samples. Overall, 45% of the men had at least one of the UV fi lters present in their seminal fl uid at detectable levels. In conclusion, chemical UV fi lters are present in men’s seminal fl uid some of which can activate the human sperm-specifi c CatSper Ca2+ channel, and thereby potentially interfere with the fer- tilization process (34). Few human studies have investigated potential side effects of UV fi lters, although human exposure is high as UV fi lters in sunscreens are rapidly absorbed from the skin. One of the UV fi lters, BP-3, has been found in 96% of urine samples in the United States, and several UV fi lters have been found in 85% of Swiss breast milk samples. It seems pertinent to evaluate whether exposure to UV fi lters contributes to possible adverse effects on endo- crine disruption (35). BIOAVAILABILITY Bioavailability, in the case of the sensitization process, refers to the fact that the substance is able to permeate the skin and can also activate a weak or non-sensitizing substance into a sensitizer. A fi rst assessment is feasible by evaluating the chemical structure and the physical properties of a substance. The skin permeation potential of a substance would be allowed, e.g., in the case of low molecular weight compounds ( 500 Da) (35). The phys- icochemical properties of the active substance and the properties of the vehicle (polarity of the solvent, particle size, and type of vehicle), exposed to the sunscreen product, affect the degree of permeation into the skin (36). JOURNAL OF COSMETIC SCIENCE 306